Amines and amides are useful and highly valuable compounds for the production of fine chemicals and pharmaceuticals. In this context, reductive amination is one of the most useful and versatile transformations for preparation of amines from carbonyl compounds in both nature and synthetic chemistry. In organic synthesis, it is attractive since aldehydes or ketones can be directly transformed in one-step to the corresponding primary or secondary alkyl amines without the need for isolation of the intermediate imines or hydroxylamines.[1]. In addition, the alkyl amine products are important due to their versatile utility as valuable synthons for pharmaceuticals and agrochemicals[2] as well as applications in chemical industries, materials science, and biotechnology.[3,4]
The Leuckart reaction is a classical process for the reductive amination of aldehydes or ketones by formamide, ammonium formate, or formic acid with formamide.[5] However, it suffers from several drawbacks (e.g. Requirement of high temperatures 150-240° C.), which lead to high consumption of energy and increase in production costs, formation of N-formyl derivatives, low chemoselectivity for synthesis of primary amines and long reaction times. Here the prolonged exposure to high temperatures of the reaction mixture inevitably leads to significant thermal decomposition of the components and consequently to lower yields of the products as well as difficulties with their isolation and purification. Moreover, production costs are increased. Therefore most of the current reductive amination procedures for the synthesis of primary amines are currently performed as two step combinations of the separate amination and reduction reactions. These two-step procedures can often take as much time as the traditional Leuckart reaction. Therefore, it is evident that there is a compelling need for fast and inexpensive methods for this classical reaction preferably under eco-friendly conditions.
Transition metal catalysts have been used for the synthesis of primary amines under the Leuckart-type reductive amination such as Rh, Ru and Ir.[6] It is noteworthy that the use of Pd/C as the catalyst leads to reduction of the carbonyl substrate to the corresponding methylene derivative.[7] However, palladium is arguably one of the most powerful and versatile transition-metal catalysts, which can be used for a variety of organic transformations and immobilized on various heterogeneous supports.[8] This could also lead to efficient recycling with consequent economic and environmental advantages. In this context, we recently developed synthetic methodology combining heterogeneous palladium catalysts with simple chiral amine co-catalysts.[9]
However, as can be seen above it would be highly challenging to develop new selective methodology for the efficient synthesis of primary amines from aldehydes or ketones using Leuckart-type conditions and a heterogeneous palladium catalyst (Scheme 1). There are serious chemoselectivity issues to take in to consideration. For example, the aldehydes 1 can be reduced either to the desired amines 2, dialkyl amine 2′, alkanes 3 or alcohols 4. Furthermore, the aldehyde substrates can oligomerize or polymerize. This also the case for ketones.

One-pot multi-component reactions are of immense significance in biological and chemical systems.[10] It is also a part of green chemistry.[10b] The catalysis of these types of reactions using multi-catalyst systems involving heterogeneous catalysts has recently been disclosed.[11] Based on this, it could be possible to develop a novel one-pot three-component transformation for the direct formation of amides starting from aldehydes, ammonium formate and a suitable acyl donor. Here the integration of enzyme-catalyzed direct amidation of the in situ generated amines with unmodified acids would be attractive.[11b] In particular, applications towards the total synthesis of natural products are desirable aims.
For example, nonovamide 6a and capsaicin 6b are pungent naturally occurring amides that have been a part of the human diet of the Americas since minimum 7500 BC (chili pepper). They activate the TRPV1 receptor[12a,b] and a wide variety of physiological and biological activities induced by them have recently been reported.[12] Thus, the synthesis of capsaicin and its analogues could be achieved by an initial efficient primary amine 2 synthesis from the aldehyde 1 using a heterogeneous metal catalyst followed by reaction with acyl chlorides to form the final products 6. Alternatively amidation can be accomplished by an enzyme-catalyzed reaction between amine 2 and different acid derivatives.
Another application of the technology is its employment for asymmetric synthesis. Here the ketone is converted to the corresponding chiral amides using the same strategies and a suitable condition. The enzyme/heterogeneous metal-catalyzed step, depending on the choice of reaction conditions, could either convert the ketone by asymmetric synthesis to the corresponding optical active amide or both this amide and an optical active amine with the opposite absolute stereochemistry.